Links between ApoE, brain cholesterol metabolism, tau and amyloid β-peptide in patients with cognitive impairment

Leoni, Valerio; Solomon, Alina; Kivipelto, Miia

doi:10.1042/bst0381021

Cited by 60 publications

(45 citation statements)

References 37 publications

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“…ApoE4 is associated with APP trafficking, inhibition of Aβ clearance and lipid (mainly cholesterol) transportation. Insulin regulates cholesterol biosynthesis and high cholesterol levels were found not only to be a risk factor for diabetes but also for AD [18,19]. Recent studies also elaborate the role of impaired insulin signaling in tau hyperphosphorylation, revealing another association between AD and diabetes [20].…”

Section: Common Features In Alzheimer's Disease and Diabetesmentioning

confidence: 95%

Overlapped Metabolic and Therapeutic Links between Alzheimer and Diabetes

Ahmad

2012

Mol Neurobiol

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Alzheimer's disease (AD) and diabetes are among the most common diseases associated with ageing. The pathology of AD is strongly associated with accumulated misfolding proteins that results in neuronal dysfunction within the brain. Diabetes, on the contrary, is characterised by altered insulin signaling that results in reduced glucose uptake, metabolic suppression of energy consuming cells and conversion of glucose to fat in the liver. Despite distinguishing features, these diseases share common elements and may in fact be viewed as fundamentally similar disorders that differ in magnitude of specific traits, primarily affected tissues and time of onset. In this review, we outline the fundamental basis of each of the two diseases and highlight similarities in their pathophysiology. Further ahead we will discuss these features in relation to the development of drugs to treat these two diseases, particularly AD, for which the development of therapeutic chemicals has proven to be particularly difficult. We conclude with comments on efforts to develop a simple organism, Caenorhabditis elegans, as a genetic model to be used to study the systems biology of diabetes and AD.

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Section: Common Features In Alzheimer's Disease and Diabetesmentioning

confidence: 95%

Overlapped Metabolic and Therapeutic Links between Alzheimer and Diabetes

Ahmad

2012

Mol Neurobiol

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“…27) Subsequent studies indicated that the stimulation of axonal extension by apo E-containing lipoproteins is mediated by the LRP1 and requires the presence of sphingomyelin in the apo E-containing lipoproteins. 66) Apo E not only plays major roles in lipid metabolism in the CNS 7,67) but also acts as a ligand for receptors in neurons. 28) Furthermore, apo E performed as an anti-inflammatory molecule through the LDL receptor and LRP1 on glia that were activated by amyloid b protein.…”

Section: Lipoproteins In the Cnsmentioning

confidence: 99%

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Hayashi

2011

Biological & Pharmaceutical Bulletin

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INTRODUCTIONFunctions of the central nervous system (CNS) are performed mainly by neurons and glia-primarily astrocytes, microglia and oligodendrocytes. It has been thought for a long time that glia only passively support neurons, but we now know that glia actively attend to assist in neuronal functions like synaptogenesis and neurotransmission. 1) Although it was believed that ca. 90% of the cells in the brain are glia and the rest of cells are neurons, Azevedo et al. recently reported that the numbers of neurons and non-neuronal cells (glia) are close to equal in human adult brain.2) Brain is the most cholesterol-rich organ in the body, and cholesterol metabolism in the CNS is tightly regulated between neurons and glia. [3][4][5][6][7] Imbalances in the metabolism of lipids, especially cholesterol, are closely linked to the development of several neurodegenerative disorders such as Alzheimer's disease, 8,9) Niemann-Pick type C disease 10) and Smith-Lemli Opitz syndrome. 11,12) In this review the regulation of lipid metabolism and the roles of glial lipoproteins in the CNS will be discussed. LIPID HOMEOSTASIS IN THE CNSThe system of lipid metabolism and transport in the CNS is different from that in peripheral tissues because the CNS is segregated from the peripheral circulation by the blood-brain barrier (BBB).13) Although lipoprotein particles can cross the BBB in vivo in Drosophila, which has a functional BBB like that in vertebrates, 14) lipoproteins in the mouse, rat and human do not cross the BBB. Consequently, since labeled cholesterol peripherally administrated was not found in the CNS of mammals, 15,16) cholesterol in the CNS is derived from de novo synthesis inside of the CNS. Furthermore, in the plasma of subjects who had liver transplantation the genotype of apolipoprotein (apo) E was that of the donor, whereas the subjects retained the own apo E genotype in the cerebrospinal fluid (CSF).17) Moreover, lipoproteins in the CNS consist of only high density lipoprotein (HDL)-like particles in contrast to the circulation which contains very low density lipoproteins (VLDL), low density lipoproteins (LDL) and HDL. It is known that the HDL-like particles in the CNS are secreted from glia (glial lipoproteins), mainly astrocytes and microglia, under normal conditions, [18][19][20] however lipoproteins can be secreted from neurons in vitro 21,22) and in vivo 23) under some specific conditions. Unesterified cholesterol is the major sterol in the adult brain, and small amounts of desmosterol and cholesteryl ester are also present. The majority (70-80%) of cholesterol in the adult brain is in myelin formed by oligodendrocytes. 24)Thus, the activity of cholesterol synthesis in the CNS is the highest during the myelinogenesis. After myelination, cholesterol synthesis continues at very low level in the CNS, and occurs mainly in astrocytes. 5,13,24) Neurons do not efficiently synthesize cholesterol and rely on external source of cholesterol from astrocytes, 25) so that neurons take up cholesterol as lipoproteins via ...

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“…1,15,18 MMD is a chronic, cerebral steno-occlusive disease with an ever-present risk of hypoxia or hemodynamic stress. Therefore, in the presence of the APOE ε2 or ε4 allele, chronic hypoxic or hemodynamic stress might trigger the occurrence of SVLs, such as microbleeds, in patients with MMD.…”

Section: Discussionmentioning

confidence: 99%

Association of apolipoprotein E gene polymorphism with small-vessel lesions and stroke type in moyamoya disease: a preliminary study

Jang

Huh

Lee

2016

JNS

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M oyaMoya disease (MMD) is a progressive cerebrovascular occlusive disorder consisting of bilateral stenosis or occlusion of the supraclinoid internal carotid artery (ICA) and its major branches, with net-like vessels in the area surrounding the circle of Willis. 27 Many studies have demonstrated a higher prevalence of asymptomatic cerebral microbleeds in patients with MMD compared with the normal population.11 In addition, a recent meta-analysis showed that a high incidence of asymptomatic cerebral microbleeds appeared to be correlated with the hemorrhagic onset type in patients with MMD.20 Kikuta et al. 12 identified the presence of multiple microbleeds as a predictor of subsequent hemorrhages in patients with MMD.abbreviatioNs APOE = apolipoprotein E; GRE = gradient-recalled echo; ICA = internal carotid artery; MMD = moyamoya disease; SVL = small-vessel lesion; T2WI = T2*-weighted imaging. obJective The present study was conducted to investigate whether microbleeds or microinfarcts are associated with apolipoprotein E (APOE) gene polymorphisms in patients with moyamoya disease (MMD), and if so, whether APOE gene polymorphisms are also associated with stroke type in patients with MMD. methods This cross-sectional, multicenter study included 86 consecutive patients with MMD who underwent T2*-weighted gradient echo or susceptibility-weighted MR imaging and 83 healthy control volunteers. Baseline clinical and radiological characteristics were recorded at diagnosis, and inter- and intragroup differences in the APOE genotypes were assessed. Multivariate binary logistic regression models were used to determine the association factors for smallvessel lesions (SVLs) and hemorrhagic presentation in patients with MMD. results There was no difference in APOE gene polymorphism and the incidence of SVLs between patients with MMD and healthy controls (p > 0.05). In the MMD group, 7 (8.1%) patients had microbleeds and 32 (37.2%) patients had microinfarcts. Microbleeds were more frequently identified in patients with hemorrhagic-type than in nonhemorrhagictype MMD (p = 0.003). APOE genotypes differed according to the presence of microbleeds (p = 0.024). APOE ε2 or ε4 carriers also experienced microbleeds more frequently than APOE ε3/ε3 carriers (p = 0.013). In the multivariate regression analysis in patients with MMD, microbleeds were significantly related to APOE ε2 or ε4 carrier status (OR 7.86;; p = 0.032) and cerebral aneurysm (OR 17.31; 95% CI 2.09-143.57; p = 0.008). Microinfarcts were independently associated with hypertension (OR 3.01; 95% CI 1.05-7.86; p = 0.007). Hemorrhagic presentation was markedly associated with microbleeds (OR 10.63; 95% CI 1.11-102.0; p = 0.041). coNclusioNs These preliminary results did not show a difference in APOE gene polymorphisms between patients with MMD and healthy persons. However, they imply that APOE gene polymorphisms may play certain roles in the presence of microbleeds but not microinfarcts in patients with MMD. A further confirmatory study is necessary to elucidate the effec...

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Links between ApoE, brain cholesterol metabolism, tau and amyloid β-peptide in patients with cognitive impairment

Cited by 60 publications

References 37 publications

Overlapped Metabolic and Therapeutic Links between Alzheimer and Diabetes

Overlapped Metabolic and Therapeutic Links between Alzheimer and Diabetes

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Association of apolipoprotein E gene polymorphism with small-vessel lesions and stroke type in moyamoya disease: a preliminary study

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